Transcutaneous β-amyloid immunization reduces cerebral β-amyloid deposits without T cell infiltration and microhemorrhage

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Abstract
Alzheimer's disease (AD) immunotherapy accomplished by vaccination with β-amyloid (Aβ) peptide has proved efficacious in AD mouse models. However, “active” Aβ vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Aβ vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated Aβ1–42 plus the adjuvant cholera toxin (CT) results in high-titer Aβ antibodies (mainly of the Ig G1 class) and Aβ1–42-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Aβ1–42 immunogen, suggesting that these unique innate immune cells participate in Aβ1–42 antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Aβ1–42 peptide plus CT. Similar to WT mice, PSAPP mice showed high Aβ antibody titers. Most importantly, t.c. immunization with Aβ1–42 plus CT resulted in significant decreases in cerebral Aβ1–40,42 levels coincident with increased circulating levels of Aβ1–40,42, suggesting brain-to-blood efflux of Aβ. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD.

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